Systematic studies are being undertaken to identify and characterize human mutants affecting the pyruvate dehydrogenase complex (PDHC). These involve the adaptation of spectrophotometric assays (using arylamine acetyltransferase of dye-coupled methods), solubilization of the enzyme from human fibroblasts and electrophoretic as well as kinetic techniques. Studies of activation and control of PDHC are also underway. Disorders being studied include lactate acidosis, Leigh disease, hereditary ataxias, and Huntington disease.